We have investigated proto-oncogene activation in chemical-induced and spontaneous rodent tumors as well as some types of human tumors. Activation of the K-ras oncogene is one important mutational event in the development of pulmonary adenocarcinoma in both human and rodent tumors. Activated K-ras genes have been detected at a high frequency in both spontaneously occurring and chemical induced lung tumors from rodents. Chemical induced rodent tumors examined include those derived from treatment with 1, 3-butadiene, tetranitromethane, methylene chloride benzo(a)pyrene, urethane ind NNK (a tobacco specific nitrosamine). Twelve of fourteen (12/14) human lung tumors examined tested positive when analyzed for transforming activity by the NIH 3T3 focus assay or the NIH 3T3 cotransfection-nude mouse tumorigenicity assay. Activated K-ras genes were detected in 40% of the human pulmonary adenocarcinomas. Eight of ten (8/10) metastatic adenocarcinomas were found to contain activated ras genes suggesting that ras gene activation may be tightly linked to the process of metastasis. N-ras, H-ras and two uncharacterized oncogenes have been detected in both adenocarcinomas and squamous cell carcinomas by the nude mouse tumorigenicity assay. A novel type of mutational activation has also been characterized in K-ras oncogenes detected in a spontaneous mouse lung tumor and in two mouse liver tumors induced by furan. Thirty base pair repeats in the second exon of K-ras were observed in these tumors, leading to tandem codon repetitions. The codon repetitions were each preceeded by a chi like element thought to promote DNA slippage or recombination. This represents a novel mechanism of proto-oncogene activation as well as a potential novel mechanism of tumor suppressor gene inactivation. Examination of proto-oncogene activation in mouse tumors induced by various environmental an occupational carcinogens (i.e., methylene chloride, chlordane, tetrachloroethylene, trichloroethylene) in both susceptible and resistant strains is also in progress. These approaches may enable us to more accurately estimate risk of cancer in humans exposed to specific classes of carcinogens.